Olesoxime protects against cisplatin-induced acute kidney injury by attenuating mitochondrial dysfunction

IF 4.1 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Peipei Wang , Jing Ouyang , Kaiqian Zhou , Dandan Hu , Shengnan Zhang , Aihua Zhang , Yunwen Yang
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Abstract

Background

Mitochondrial dysfunction is a critical factor in the pathogenesis of acute kidney injury (AKI). Agents that ameliorate mitochondrial dysfunction hold potential for AKI treatment. The objective of this study was to investigate the impact of olesoxime, a novel mitochondrial-targeted agent, on cisplatin-induced AKI.

Methods

In vivo, a cisplatin-induced AKI mouse model was established by administering a single intraperitoneal dose of cisplatin (25 mg/kg) to male C57BL/6 mice for 72 hours, followed by gavage of either olesoxime or a control solution. In vitro, human proximal tubular HK2 cells were cultured and subjected to treatments with cisplatin, either in the presence or absence of olesoxime.

Results

In vivo, our findings demonstrated that olesoxime administration significantly mitigated the nephrotoxic effects of cisplatin in mice, as evidenced by reduced blood urea nitrogen (BUN) and serum creatinine (SCr) levels, improved renal histopathology, and decreased expression of renal tubular injury markers such as kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). Furthermore, olesoxime administration markedly reduced cisplatin-induced apoptosis, inflammation, and oxidative stress in the kidneys of AKI mice. Additionally, olesoxime treatment effectively restored mitochondrial function in the kidneys of AKI mice. In vitro, our results indicated that olesoxime treatment protected against cisplatin-induced apoptosis and mitochondrial dysfunction in cultured HK2 cells. Notably, cisplatin's anticancer effects were unaffected by olesoxime treatment in human cancer cells.

Conclusion

The results of this study suggest that olesoxime is a viable and efficient therapeutic agent in the treatment of cisplatin-induced acute kidney injury presumably by alleviating mitochondrial dysfunction.
奥利昔肟通过减轻线粒体功能障碍防止顺铂引起的急性肾损伤。
线粒体功能障碍是急性肾损伤(AKI)发病的关键因素。改善线粒体功能障碍的药物具有治疗AKI的潜力。本研究的目的是研究磺肟(一种新型线粒体靶向药物)对顺铂诱导AKI的影响。方法在体内,雄性C57BL/6小鼠单次腹腔注射顺铂(25 mg/kg) 72小时,然后灌胃磺肟或对照溶液,建立顺铂诱导AKI小鼠模型。在体外,人近端小管HK2细胞被培养并接受顺铂治疗,在存在或不存在磺肟的情况下。结果在小鼠体内,我们的研究结果表明,磺肟给药显著减轻了顺铂的肾毒性作用,这可以通过降低血尿素氮(BUN)和血清肌酐(SCr)水平、改善肾脏组织病理学、降低肾小管损伤标志物如肾损伤分子1 (KIM-1)和中性粒细胞明胶酶相关脂钙蛋白(NGAL)的表达来证明。此外,磺肟给药可显著减少顺铂诱导的AKI小鼠肾脏细胞凋亡、炎症和氧化应激。此外,磺肟治疗有效地恢复了AKI小鼠肾脏的线粒体功能。在体外,我们的研究结果表明,在培养的HK2细胞中,磺肟治疗可以防止顺铂诱导的细胞凋亡和线粒体功能障碍。值得注意的是,在人类癌细胞中,顺铂的抗癌作用不受磺肟治疗的影响。结论磺肟可能通过减轻线粒体功能障碍,是治疗顺铂所致急性肾损伤的有效药物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Biomedical Journal
Biomedical Journal Medicine-General Medicine
CiteScore
11.60
自引率
1.80%
发文量
128
审稿时长
42 days
期刊介绍: Biomedical Journal publishes 6 peer-reviewed issues per year in all fields of clinical and biomedical sciences for an internationally diverse authorship. Unlike most open access journals, which are free to readers but not authors, Biomedical Journal does not charge for subscription, submission, processing or publication of manuscripts, nor for color reproduction of photographs. Clinical studies, accounts of clinical trials, biomarker studies, and characterization of human pathogens are within the scope of the journal, as well as basic studies in model species such as Escherichia coli, Caenorhabditis elegans, Drosophila melanogaster, and Mus musculus revealing the function of molecules, cells, and tissues relevant for human health. However, articles on other species can be published if they contribute to our understanding of basic mechanisms of biology. A highly-cited international editorial board assures timely publication of manuscripts. Reviews on recent progress in biomedical sciences are commissioned by the editors.
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